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At least 19 recordsLinked to original sources
PubMed1981

Effects of nafoxidine on the luteinizing hormone surge: temporal distribution of estrogen receptors and induction of cytoplasmic progestin receptors in the hypothalamus-preoptic area, pituitary, and uterus of the immature rat.

The antiestrogen nafoxidine 1-(2-[P-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]pyrrolidine hydrochloride; 2 mg/rat), blocked LH surges induced by Silastic implants containing estradiol (E2) in oil (150 micrograms/ml) in the immature female rat and had no stimulatory effect on gonadotropin secretion by itself. Furthermore, the administration of progesterone (P) to rats primed for 24 h with nafoxidine alone or nafoxidine plus E2 did not lead to premature and enhanced LH surges (facilitation) as it does in E2-primed animals. Pituitary LH content was depleted by 30-50% after E2-induced or P-facilitated LH surges, but was unchanged after the administration of nafoxidine or nafoxidine plus E2. To investigate the cellular mechanisms involved, levels of total cytoplasmic and nuclear estrogen receptors and cytoplasmic progestin receptors in the hypothalamus-preoptic area (HPOA), pituitary, and uterus were measured by [3H]E2 or [3H]R5020 (3H-labeled 17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) exchange assays at various times after the administration of E2 and /or nafoxidine. The ability of nafoxidine to bind in vitro to cytoplasmic or nuclear estrogen receptors was, respectively, 4% and 2% (HPOA), 5% and 6% (pituitary), and 1% and 2% (uterus) relative to E2 (100%). After the injection of nafoxidine or the insertion of E2 implants, cytoplasmic estrogen receptors were depleted with a similar time course and remained depressed for at least 48 h in both the HPOA and pituitary. In the uterus, the antiestrogen prevented the replenishment of cytoplasmic estrogen receptors observed in response to E2. Nuclear estrogen receptor levels in the HPOA and pituitary peaked 1 h after E2 and subsequently declined to a plateau from 24-48 h (at 2-4 times the levels found in untreated rats). After nafoxidine, accumulation of these receptors in the nucleus was more gradual and prolonged. Absolute levels of estrogen receptors translocated to the nucleus by E2 or nafoxidine were comparable. E2 treatment led to a substantial induction of cytoplasmic progestin receptors (approximately 2-fold in the HPOA, approximately 4-fold in the pituitary, and approximately 7-fold in the uterus after 48 h), and this process was considerably inhibited by nafoxidine. These results support the notions that antagonism by nafoxidine of estrogen action may be due to a defective association of the antiestrogen-receptor complex with nuclear sites, ad progestin receptor induction may be a prerequisite for the facilitation of gonadotropin surges by P.

Animals↗
PubMed1977

Interaction of the anti-oestrogen, nafoxidine hydrochloride, with the soluble nuclear oestradiol-binding protein in chick liver.

Nafoxidine hydrochloride (Upjohn, 11100A)injected with oestradiol into immature chicks inhibits the hormone-induced increase in [3H]oestradiol-binding activity in salt extracts of liver nuclei as well as the subsequent production by liver of egg-yolk phosphoprotein. Substantial inhibition of both oestradiol-induced responses is seen when nafoxidine is given in a dose approximately equimolar with that of oestradiol. In vitro nafoxidine competitively inhibits binding of [3H]oestradiol in nuclear extracts. The Ki for the inhibition is 43 nM, which indicates an affinity of nafoxidine for the binding protein about 4% of that of oestradiol. The inhibitory action of nafoxidine in vivo thus is more potent than the relative binding affinity determined in vitro might indicate. One possible explanation is that the primary site of nafoxidine action is at a point proximal to nuclear receptor interaction. Nafoxidine injected alone into the chick does not induce phosphoprotein synthesis, but it does increase [3H]oestradiol-binding activity in extracts of liver nuclei to a limited extent. No differences in the properties of the oestradiol-binding activity in extracts from nafoxidine-treated chicks or from oestradiol-treated chicks were detected. Chick liver cytosol does not contain detectable high-affinity oestradiol-binding activity. A low-affinity oestradiol-binding component with a sedimentation coefficient of 3.5S was found, but it was unaffected by treatment of chicks with earlier nafoxidine or oestradiol. The results suggest a difference in the mechanism of oestradiol action in the chick liver and in the widely studied rat uterus, on which the usual model for oestradiol action is largely based.

Animals↗
PubMed1976

Therapeutic value of nafoxidine hydrochloride in the treatment of advanced carcinoma of the human breast.

Nafoxidine hydrochloride can provide additional palliation to patients who responded to previous endocrine ablation and had tumors containing an estrogen receptor. In the present study, 24 patients were evaluated for their response to nafoxidine therapy, 180 to 240 milligrams given orally per day. When tumor response was obtained, doses were reduced to 60 to 120 milligrams every other day or longer without loss of control. In the estrogen receptor positive group, eight of ten patients responded objectively to nafoxidine, while all seven estrogen receptor negative patients progressed with this therapy. These results demonstrated that nafoxidine is effective in the treatment of estrogen receptor positive cutaneous disease. These results demonstrated that nafoxidine is effective in the treatment of estrogen receptor positive cutaneous disease. Patients with lesions to other sites should receive cytoxic agents along with nafoxidine. Alternative therapy to nafoxidine should be considered for patients in whom the tumors contain negligible estrogen receptor.

Adult↗
PubMed2001

Inhibition of volume-regulated anion channels in cultured endothelial cells by the anti-oestrogens clomiphene and nafoxidine.

1. We have used the whole-cell patch clamp technique to study the effect of the partial anti-oestrogens clomiphene and nafoxidine, the pure anti-oestrogens ICI 182,780 and RU 58,668 and the oestrogen ss-estradiol, on the volume-regulated anion channel (VRAC) in cultured pulmonary artery endothelial (CPAE) cells. 2. In contrast to the pure anti-oestrogens and ss-estradiol, clomiphene and nafoxidine potently inhibited the volume-sensitive chloride current, I(Cl,swell), activated by challenging CPAE cells with a 25% hypotonic solution. For clomiphene, the estimated IC(50) and Hill coefficient were 1.03+/-0.14 microM and 1.40+/-0.21 respectively. In the case of nafoxidine, these values were 1.61+/-0.29 microM and 1.24+/-0.19. 3. The inhibition induced by the pure enantiomers of clomiphene, zuclomiphene and enclomiphene, was not different from that of the racemic mixture, indicating that the interaction between clomiphene and VRAC is not stereoselective. 4. Clomiphene and nafoxidine inhibited proliferation of CPAE cells. Half-maximal inhibition was found at 1.98+/-0.17 and 1.66+/-0.21 microM respectively, concentrations similar to those for half-maximal block of VRAC. 5. In conclusion, the nonsteroidal partial anti-oestrogens nafoxidine and clomiphene are potent inhibitors of volume-regulated anion channels. The inhibition by clomiphene is not stereoselective and occurs at concentrations close to therapeutically relevant concentrations. Finally, both drugs inhibit the proliferation of endothelial cells.

Cell Division↗
PubMed1996

Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats.

For the first time, four well-characterized compounds from four distinct chemical classes were directly compared for efficacy and potency in hone, uteri, lipids, and adipose tissues in an ovariectomized model with 6 month old rats. Five weeks of oral dosing confirmed that ethynyl estradiol, tamoxifen, and raloxifene are potent inhibitors of the loss in volumetric bone mineral density (BMD, mg/cc) induced by ovariectomy, as measured by computed tomography. In the metaphysis of distal femora from ovariectomized rats, analysis showed a significant 12-20% decrease (P< 0.01) in the BMD. Linear regression analysis was used to calculate half-maximal efficacious doses for ethynyl estradiol ED(50) =0.04mg /kg, which was threefold more potent than tamoxifen, which in turn was threefold more potent than raloxifene, which was more efficacious than nafoxidine. In the uterus, raloxifene had minimal effects on the endometrium and smaller effects on uterine eosinophil peroxidase activity than nafoxidine, tamoxifen, or estrogen, respectively. Estrogen was the most potent in reducing cholesterol levels in ovariectomized rats, whereas tamoxifen and nafoxidine were more effective than raloxifene in blocking gain in body weight. Distinct compounds had advantages in the management of bone, uterine, serum cholesterol, and adipose tissues after ovariectomy. The distinct pattern of pharmacological effects may be best understood in terms of their respective chemical structure, specifically estrogens, benzothiophenes (raloxifene), dihydronapthylenes (nafoxidine), and triphenylethylenes (tamoxifen). These data point to advantages of separate compounds in the management of bone, uterine, serum cholesterol, and adipose tissues after estrogen deficiency, and show that the benzothiophene raloxifene has potentially important advantages over estrogen, tamoxifen, or nafoxidine in the uterus.

Adipose Tissue↗
PubMed1978

Selective blockade of estrogen-induced uterine responses by the antiestrogen nafoxidine.

The response of the immature rat uterus to the antiestrogen, nafoxidine (Upjohn U-11, 100A), is maximum at a dose of 5 micrograms. This dose of nafoxidine sustains the uterine response for at least 72 h. After treatment with 5 micrograms nafoxidine for 24 h, uterine cytosol contains approximately one half the total number of estrogen receptors originally present in uteri of untreated animals, and uterine nuclei also contain approximately one half the receptors originally present in unstimulated tissue. The total amount of uterine estrogen receptor, however, is not altered 24 h after treatment with nafoxidine relative to saline-treated controls, while estradiol treatment doubles the total amount of receptor relative to controls. Pretreatment with 5 micrograms nafoxidine for 24 h does not block the uterine response occurring 4 h after the subsequent administration of estradiol, but does block the uterine response occurring 24 h after the subsequent administration of estradiol. These results suggest that uterine nuclei contain different acceptor sites for regulating short term and long term uterine responses to estrogen.

Animals↗
PubMedDate not supplied

Nafoxidine modulates the expression of matrix-metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in endothelial cells.

During angiogenesis, proteases and their inhibitors interact in the remodelling of the basement membrane. It has been demonstrated that nafoxidine has antiangiogenic activity in the chick egg chorioallantoic membrane assay, but the precise mechanism of action is unknown. We have analyzed the effect of the partial estrogen antagonist nafoxidine on human umbilical vein endothelial cells (HUVEC). Our data indicated that in nafoxidine-treated endothelial cells MMP-2 was activated. Nafoxidine upregulated, in a dose-dependent manner, the secretion of a 66 kDa TIMP-1 dimer, that lacks anti-MMP activity and inhibited angiogenesis in the endothelial cord formation assay. We can postulate that nafoxidine induces an increase in TIMP-1, which has antiangiogenic activity in the late stages of tube formation, independent of its capacity to inhibit MMPs.

Angiogenesis Inhibitors↗
PubMed1977

Clinical trial of nafoxidine in adrenalectomized patients with advanced breast cancer.

Antiestrogen compounds are relatively new in the treatment of breast cancer. A clinical trial of Nafoxidine therapy is being pursued in our institution. In a selected group of patients with metastatic breast cancer who had, in the past, undergone adrenalectomy, Nafoxidine therapy produced objective tumor regression in six out of ten patients. Of the six patients whose tumors contained demonstrable estrogen receptors, four showed regression (67%), one patient had stable disease, and one showed tumor progression. Of the four patients in whom estrogen receptor estimation was not done, two had, in the past, shown regression after endocrine therapy and they also showed regression of tumor with Nafoxidine therapy. In patients with metastatic breast carcinoma, who have undergone adrenalectomy in the past, a therapeutic trial with Nafoxidine may be worthwhile particularly in patients who have demonstrable estrogen receptor in the tumor of those who have in the past shown regression of tumor after endocrine therapy.

Adrenalectomy↗
PubMed1974

Antioestrogens in treatment of breast cancer: value of nafoxidine in 52 advanced cases.

The synthetic non-steroidal antioestrogen nafoxidine (U-11, 100A) was given by mouth to 52 women with locally advanced or metastatic breast cancer, in 85% of whom the disease had become resistant to, or relapsed after, previous endocrine treatment. The objective response rate (complete or partial regression of disease) among 48 cases treated for at least four weeks was 37%. Tumours in soft tissue seemed to respond better than skeletal metastases. The patients in all but one of the 52 cases were postmenopausal. Those who had had an objective response to previous hormone treatment had a greater chance of deriving benefit from nafoxidine than those who had been resistant to hormone treatment.Side effects of nafoxidine were dryness of skin, increased loss of scalp hair, and heightened sensitivity to sunlight. None were serious, and they could be lessened by protection from solar radiation or a decrease in dosage. No obvious depression of thyroid or adrenal function or obvious water retention or masculinization was seen. Cataract was a possible complication.This clinical trial was preceded by laboratory studies in which a transplantable oestrogen-dependent tumour in the Syrian hamster was notably inhibited by the administration of nafoxidine. This experimental model may prove useful in screening potentially useful antioestrogenic agents against breast cancer before a human trial.

Adult↗
PubMed1988

Effect of neonatal exposure to the antioestrogens nafoxidine and CI-628 upon the development of the uterus in the prepubertal rat.

Neonatal Sprague-Dawley rats were injected with the antioestrogens nafoxidine or CI-628 on Day 3 of life alone or in combination with oestradiol benzoate 24 h later. Oestrogen-stimulated glucose oxidation and cytoplasmic oestrogen binding sites of the uteri were assessed at 21-23 days of age. Neither antioestrogen antagonized the prepubertal uterine impairments produced by neonatal oestradiol treatment. Both antioestrogens administered alone produced deficits which mimicked those produced by neonatal oestrogenization. However, the agonist property of each antioestrogen was differentially expressed: treatment with CI-628 reduced prepubertal oestrogen binding sites in the uterus, but nafoxidine exposure decreased the sensitivity of the uterus to oestradiol stimulation of glucose oxidation. It is postulated that CI-628 directly affects the uterus to reduce production of oestrogen receptor protein, while nafoxidine affects the development of the uterine phosphogluconate oxidative pathway indirectly through impaired ovarian function. However, antioestrogens blocked the neonatal oestradiol-induced reduction in the oestrogen-stimulated production of actomyosin in the adult uterus. Therefore, while both CI-628 and nafoxidine are clearly agonists in the neonatal rat, each appears to exhibit cell-specific agonist and antagonist properties.

Actomyosin↗
PubMed1976

Nafoxidine--an antiestrogen for the treatment of breast cancer.

Nafoxidine is a nonsteroidal antiestrogen available as an investigational agent from the Investigational Drug Branch of the National Cancer Institute. It has been used effectively in the treatment of breast cancer patients. A cumulative response rate of 31% is reported for a total of 200 patients treated with this drug. Most patients have been treated with a dose of 60 mg three times a day. Side effects include dryness of skin, photosensitivity reactions and, less commonly, partial hair loss. There is a strong correlation of response to nafoxidine with the presence of estrogen receptor in the tumor and also with the response to previous hormonal treatment. Nafoxidine is a useful addition to the list of hormonal treatments in the therapy of breast cancer.

Animals↗
PubMed1983

Nafoxidine administered to newborn female GR mice arrests the development of their mammary glands.

Mice of the GR strain develop many hormone-dependent mammary tumors in response to estrogen and progesterone stimulation. Since this strain is so sensitive to steroid hormones, we administered a single dose of the antiestrogen Nafoxidine to female GR mice within 24 hours after their birth. This treatment arrested the development of their mammary glands and when the mice were adults, 10 weeks old, they did not cycle normally but were in a state of persistent estrus. Whole mounts of mammary glands from Nafoxidine-treated mice revealed cystic areas within some ducts and bulbous swellings at the ends of others. No hyperplastic alveolar nodules (HAN) were identified in the glands. In contrast, a single dose of 17 beta estradiol administered within 24 h after birth, resulted in a highly branched gland displaying typical end buds, a few alveoli and more HAN than were observed in glands of control adult mice of the same strain. Thus Nafoxidine treatment not only arrested the development of the mammary glands in female GR mice (causing them to appear "masculinized") but it also produced abnormalities within the glands.

Animals↗
PubMed1986

Nafoxidine possesses antitumor activity against an ascitic hepatoma.

Nafoxidine an antiestrogen is shown to possess antitumor activity against the Zajdela ascitic hepatoma. Nafoxidine prolonged the survival time of the rats injected with the tumor cells; complete regression of the tumor was observed when rats bearing a 3-day-old tumor were injected with this compound. Nafoxidine (Naf) also showed cytotoxic effects against the hepatoma cells in vitro. Naf competed with the binding of labelled estradiol to the tumor cells.

Animals↗
PubMed1981

Nafoxidine-responsive uterine protein: further characterization and distinction from the "estrogen-induced" protein (IP).

In a previous paper, we reported that nafoxidine (UA) stimulated the synthesis of a uterine protein showing the same electrophoretic mobility as the "estrogen-induced protein" (E2-IP) first described by Notides and Gorski. In the present work, we analyzed the IP-containing electrophoretic zone by SDS polyacrylamide-gel electrophoresis, and found that estradiol-17 beta (E2) and nafoxidine stimulated the synthesis of different proteins. As expected, estradiol-17 beta stimulated the synthesis of the E2-IP of 46 000 Mr. On the other hand, UA stimulated the synthesis of 27 000 and 30 000 Mr proteins (UA-IP). These UA-IP were not precipitated by an antiserum raised against E2-IP. Therefore, UA-IP appear to be independent entities and not degradation or precursor products of E2-IP. Both UA-IP are constitutively present in the uterus and even in higher relative amounts in rat brain. The present finding, that an "anti-estrogen", such as nafoxidine, stimulates the synthesis of different proteins than estrogen, provides a new approach to the study of the molecular mechanism of estrogen action.

Animals↗
PubMed1976

RNA polymerase activity and uterine growth: Differential stimulation by estradiol, estriol, and nafoxidine.

We have shown previously that estradiol, estriol, and Nafoxidine (Upjohn 11, 100A) have differential effects on uterine growth and that these effects are associated with the retention of the estrogen receptor by the nucleus. In order to examine these relationships further, we have studied the effect of these hormones on endogenous nuclear RNA polymerase I and II in the immature rat uterus. All three compounds caused a rapid elevation in polymerase II activity that reached a peak by the first hour and declined to almost control levels by 2 h after the injection. This transient peak in polymerase II activity was followed by a second elevation by the fourth hour in estradiol- and Nafoxidine-treated animals which was not observed in estriol-treated rats. The activity of polymerase I increased monotonically to very high levels by 4 h and was maintained 12 h or longer in estradiol- and Nafoxidine-treated animals. A similar elevation was observed in estriol-treated rats but the activity declined very rapidly to control levels by 12 h. The second elevation in polymerase II activity and the sustained stimulation of polymerase I activity were correlated with the stimulation of true uterine growth. These data confirm our previous suggestion that long-term nuclear retention of the receptor is a requirement for true uterine growth and suggest that an obligatory response in the production of true growth is the stimulation of a second rise in polymerase II activity and an elevated and sustained activity of polymerase I.

Aging↗
PubMed1980

Crystal and molecular structure of nafoxidine and stereochemical features of anticancer antiestrogens.

We have determined the molecular structure of the anticancer antiestrogen nafoxidine and compared its three-dimensional structure with two other clinically useful antiestrogens in order to delineate stereochemical parameters in these compounds. Crystals of nafoxidine hydrochloride-ethanol are monoclinic with cell dimensions a = 17.040, b = 7.967, c = 25.260 A, beta = 123.7 degrees, and space group P21/c with four formula units per cell. The structure was solved by direct phasing methods and refined to a discrepancy index of 0.068. The methoxyphenyl and phenyl rings are trans to each other relative to the ethylene bond, and the substituted amine-aryl ether chain has an extended conformation. Stereoscopic superposition drawings and tabular data are given to show structural similarities and difference in nafoxidine, clomiphene, and tamoxifen, the three antiestrogens with with demonstrated clinical efficacy in the management of metastatic mammary carcinoma.

Antineoplastic Agents↗
PubMed1975

Comparative trial of nafoxidine and ethinyloestradiol in advanced breast cancer: an E.O.R.T.C. study.

A randomized clinical trial of nafoxidine, a non-steroidal oestrogen antagonist, and ethinyloestradiol in postmenopausal patients with advanced breast cancer produced objective remissions in 31% of 49 women receiving nafoxidine and in 14% of 49 receiving ethinyloestradiol. The differences in remission rates was almost significant (0.05 less than P less than 0.10). Life-threatening complications were more frequent with ethinyloestradiol than with nafoxidine but the latter produced specific toxic reactions on skin and hair that may limit its practical usefulness. Synthetic oestrogen antagonists may occupy a privileged place in the treatment of breast cancer, and other representatives of this new class of compounds should be accurately assessed in randomized clinical trials.

Administration, Oral↗
PubMed1977

Female steroid hormones and lipoprotein synthesis in the cockerel: effects of progesterone and nafoxidine on the estrogenic stimulation of very low density lipoproteins (VLDL) synthesis.

Since progesterone is known to modulate the effects of estradiol in a number of organ systems, we have studied the effects of the two hormones on very low density lipoproteins (VLDL) synthesis in the cockerel. We have also examined the effect of an estrogen antagonist, nafoxidine-HCl, on the process. When three week-old cockerels were treated with a single injection of estradiol (1 mg) or estradiol (1 mg) + progesterone (2 mg), plasma VLDL increased within 5 h, reached a peak at 48 h and returned to baseline values at 68 h. There was no significant difference between estradiol or estradiol + progesterone treated animals. Liver slices were prepared from similarly treated animals and incubated in vitro with L-[3H]lysine for 2 h. Following homogenization and centrifugation at 105,000 X g, newly synthesized VLDL were quantitiated in the supernatant fluid by immunoprecipitation with a monospecific antibody. Radioactivity incorporated into VLDL was found to increase from low baseline levels to a peak at about 17 h after treatment. There was, again, no significant difference between estradiol and estradiol + progesterone-treated animals. Estrogen priming or progesterone pretreatment also did not significantly alter the VLDL biosynthetic response in liver slices to estradiol alone or in combination with progesterone. When the estrogen-antagonist nafoxidine-HCl (5 mg) was administered simultaneously with estradiol (1 mg), it totally inhibited the VLDL biosynthetic response in liver slices in vitro. The interaction of estradio, progesterone and nafoxidine-HCl on the hepatic synthesis of VLDL should serve as a valuable model for the study of VLDL synthesis and its regulation as well as the mode of action of the sex steroid hormones in the liver.

Animals↗